Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139 DOI 10.1186/s13023-015-0349-z
RESEARCH
Open Access
Review and comparison of clinical evidence submitted to support European Medicines Agency market authorization of orphan-designated oncological treatments Julie Winstone1, Shkun Chadda1*, Stephen Ralston1 and Peter Sajosi2
Abstract Background: Clinical trials for treatments indicated for orphan diseases may be limited due to the low prevalence of such diseases; this can result in implications for both regulatory and health economic perspectives. This study assessed the pivotal clinical evidence packages submitted to support applications for European Medicines Agency (EMA) marketing authorizations for treatments for orphan conditions, in relation to the size of the eligible patient population. Methods: Approved treatments for EMA-designated orphan conditions (defined as life-threatening or chronically debilitating conditions that affect ≤5/10,000 people) were identified from the EMA web site. All treatments reviewed were included in anatomical therapeutic chemical (ATC) category L (antineoplastic and immunomodulating drugs): this category was selected because it is the largest ATC category, containing almost 50 % of all approved orphan-designated products. Treatments were reviewed if they had been approved within the past 7 years and had been evaluated in a controlled trial using at least one survival-based clinical endpoint. Treatments were compared in terms of patient-years (accumulated duration of follow-up), the number of patients in the pivotal trials and disease prevalence. Results: As of 1 February 2014, 68 treatments had been approved for orphan-designated conditions, of which 30 belonged to ATC category L and 14 met all inclusion criteria. The number of patients in the pivotal trials ranged from 162 to 846 (median 485). In terms of patient-years, the longest duration of follow-up was seen in the pivotal trial of mifamurtide in osteosarcoma, which had 4068 patient-years; excluding this trial, follow-up ranged from 308 to 2906 patient-years (median 1796 years). Osteosarcoma had the second smallest eligible patient population (0.5/10,000 persons) of the reviewed treatments. Conclusions: Clinical trials of orphan treatments are often limited by low patient numbers and inadequate follow-up. Pooling of expertise in single centres and the establishment of rare disease reference networks and patient registries may facilitate appropriate trial design for orphan-designated treatments. This analysis found that the pivotal clinical trial for mifamurtide in osteosarcoma had the largest number of patient-years of follow-up, despite a small eligible patient population, showing that it is possible to conduct studies with an adequate patient population size and duration of follow-up in patient-years, and a comparative design with clinical, survival-based, endpoints. Keywords: European Medicines Agency, Clinical trials, Mifamurtide, Orphan disorders, Orphan treatments, Osteosarcoma
* Correspondence: [email protected] 1 SIRIUS Market Access, 58 St Kilda Rd, London W13, UK Full list of author information is available at the end of the article © 2015 Winstone et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139
Background Although definitions of orphan diseases vary, it is generally accepted in most countries that such disorders affect between 1 and 8 individuals per 10,000. Within the European Union (EU), orphan conditions are defined by the European Medicines Agency (EMA) as lifethreatening or chronically debilitating conditions that affect no more than 5 in 10,000 people (equivalent to approximately 250,000 or fewer people for each condition) in the EU [1–3]. There are difficulties in balancing the urgent need for drugs to treat rare diseases with the requirements for guaranteed quality, efficacy and safety and, when necessary, making comparisons with existing therapies. Reliable methods of evaluating drugs in small numbers of patients are problematic, adding to difficulties in producing high-quality dossiers, despite incentives for pharmaceutical companies to develop such products and the use of less stringent criteria for trials of drugs with designated orphan indications [4]. These problems are evident even when the efficacy of a potential treatment is well established in other indications [1]. For these reasons, clinical data submitted to support an application for marketing authorization of treatments for orphan conditions may often be less robust than is the case for treatments for non-orphan common conditions. In a study in 2006, for example, 10 of 18 (55 %) approved orphan-designated treatments were authorized ‘under exceptional circumstances’, indicating that the clinical dossiers were incomplete and that further studies would be needed to maintain the marketing authorization [4]. Overall, only nine of the approved treatments (50 %) were supported by RCT data: five were supported only by uncontrolled Phase II studies, two by uncontrolled open-label studies, and one by a literature analysis alone. Other limitations of the submitted data included the use of surrogate endpoints and inadequate durations of follow-up in relation to the natural history of the disease. A subsequent study by the same authors suggested that this situation persisted throughout the first decade after implementation of orphan drug legislation in the EU [5]. The limitations of the clinical evidence submitted to support marketing authorizations for orphan treatments have a number of implications. Poorly designed pivotal trials may contribute to a low rate of success for such applications both in the EU [4, 6] and the USA [7]. Furthermore, limited pivotal trial data, together with the high cost of many orphan treatments, may create difficulties in terms of reimbursement and market access [1, 8, 9]. As the number of orphan-designated treatments entering clinical practice increases, it is possible that the data supporting an application for marketing authorization may increase. Indeed, it has recently been suggested that submission of objective data on the natural
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history of a disease and the potential impact of the proposed new treatment could form an additional criterion for decision-making on market access and reimbursement policies [10]. A further consideration is that marketing authorizations based on limited clinical data could potentially expose the patient to increased risk of adverse events or lack of efficacy, compared with non-orphan treatments [11]. In view of these issues, the present study was performed to evaluate the pivotal clinical evidence packages presented in the European Public Assessment Report for orphan-designated treatments with an EMA marketing authorization.
Methods This study reviewed the clinical evidence packages for treatments approved by the EMA. All treatments included in the review belong to anatomical therapeutic chemical (ATC) category L (antineoplastic and immunomodulating agents); this category was chosen because it is the largest ATC category, containing almost 50 % of all orphan-designated treatments that have received marketing authorization from the EMA. Treatments were eligible for inclusion in the review if they had been approved after 31 December 2006 and had been evaluated in a comparative trial using at least one survivalbased clinical endpoint as opposed to short-term surrogate endpoints. The time limit was imposed to ensure that all included treatments had been evaluated by the EMA using similar criteria: it is possible that older treatments might have been evaluated using less stringent criteria than recently approved treatments. Similarly, the requirement for comparative studies using survivalbased endpoints was imposed because such studies can be considered the ‘gold standard’ for clinical trials in oncology and are recommended in United States Food and Drug Administration guidance [12]. Eligible treatments were compared in terms of the number of patients included in pivotal (‘main’) clinical trials submitted to support the application for marketing authorization, the cumulative duration of follow-up in the pivotal trials, expressed in patient-years, and the prevalence of the orphan condition. The number of patient-years of follow-up was calculated by multiplying the total number of patients in each study (across all treatment arms) by the study duration; where the study duration was not reported explicitly, Kaplan-Meier curves or data tables were used to estimate the duration of follow-up. Prevalence data for each orphan-designated condition were obtained from the relevant EMA Committee for Orphan Products public summary of opinion [3]: where these data were provided as the number of affected patients in the EU, this was converted to the rate per 10,000 based on the EU population at the time of orphan designation.
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139
In addition to patient numbers and duration of followup, the quality of the pivotal trials for all orphan products approved by the EMA since 31 December 2006 was assessed by means of the Jadad scoring system [13]. In this system, a maximum of two points each are given for appropriate randomization and blinding, and a further point is given if all patients are adequately accounted for; thus, the maximum possible Jadad score is 5.
Results As of 1 February 2014, 68 treatments with 87 indications had received an EMA marketing authorization for orphan-designated conditions. The prevalence of the orphan indications varied markedly, from 0.00125/10,000 persons for N-acetylglutamate synthetase deficiency to
RESEARCH
Open Access
Review and comparison of clinical evidence submitted to support European Medicines Agency market authorization of orphan-designated oncological treatments Julie Winstone1, Shkun Chadda1*, Stephen Ralston1 and Peter Sajosi2
Abstract Background: Clinical trials for treatments indicated for orphan diseases may be limited due to the low prevalence of such diseases; this can result in implications for both regulatory and health economic perspectives. This study assessed the pivotal clinical evidence packages submitted to support applications for European Medicines Agency (EMA) marketing authorizations for treatments for orphan conditions, in relation to the size of the eligible patient population. Methods: Approved treatments for EMA-designated orphan conditions (defined as life-threatening or chronically debilitating conditions that affect ≤5/10,000 people) were identified from the EMA web site. All treatments reviewed were included in anatomical therapeutic chemical (ATC) category L (antineoplastic and immunomodulating drugs): this category was selected because it is the largest ATC category, containing almost 50 % of all approved orphan-designated products. Treatments were reviewed if they had been approved within the past 7 years and had been evaluated in a controlled trial using at least one survival-based clinical endpoint. Treatments were compared in terms of patient-years (accumulated duration of follow-up), the number of patients in the pivotal trials and disease prevalence. Results: As of 1 February 2014, 68 treatments had been approved for orphan-designated conditions, of which 30 belonged to ATC category L and 14 met all inclusion criteria. The number of patients in the pivotal trials ranged from 162 to 846 (median 485). In terms of patient-years, the longest duration of follow-up was seen in the pivotal trial of mifamurtide in osteosarcoma, which had 4068 patient-years; excluding this trial, follow-up ranged from 308 to 2906 patient-years (median 1796 years). Osteosarcoma had the second smallest eligible patient population (0.5/10,000 persons) of the reviewed treatments. Conclusions: Clinical trials of orphan treatments are often limited by low patient numbers and inadequate follow-up. Pooling of expertise in single centres and the establishment of rare disease reference networks and patient registries may facilitate appropriate trial design for orphan-designated treatments. This analysis found that the pivotal clinical trial for mifamurtide in osteosarcoma had the largest number of patient-years of follow-up, despite a small eligible patient population, showing that it is possible to conduct studies with an adequate patient population size and duration of follow-up in patient-years, and a comparative design with clinical, survival-based, endpoints. Keywords: European Medicines Agency, Clinical trials, Mifamurtide, Orphan disorders, Orphan treatments, Osteosarcoma
* Correspondence: [email protected] 1 SIRIUS Market Access, 58 St Kilda Rd, London W13, UK Full list of author information is available at the end of the article © 2015 Winstone et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139
Background Although definitions of orphan diseases vary, it is generally accepted in most countries that such disorders affect between 1 and 8 individuals per 10,000. Within the European Union (EU), orphan conditions are defined by the European Medicines Agency (EMA) as lifethreatening or chronically debilitating conditions that affect no more than 5 in 10,000 people (equivalent to approximately 250,000 or fewer people for each condition) in the EU [1–3]. There are difficulties in balancing the urgent need for drugs to treat rare diseases with the requirements for guaranteed quality, efficacy and safety and, when necessary, making comparisons with existing therapies. Reliable methods of evaluating drugs in small numbers of patients are problematic, adding to difficulties in producing high-quality dossiers, despite incentives for pharmaceutical companies to develop such products and the use of less stringent criteria for trials of drugs with designated orphan indications [4]. These problems are evident even when the efficacy of a potential treatment is well established in other indications [1]. For these reasons, clinical data submitted to support an application for marketing authorization of treatments for orphan conditions may often be less robust than is the case for treatments for non-orphan common conditions. In a study in 2006, for example, 10 of 18 (55 %) approved orphan-designated treatments were authorized ‘under exceptional circumstances’, indicating that the clinical dossiers were incomplete and that further studies would be needed to maintain the marketing authorization [4]. Overall, only nine of the approved treatments (50 %) were supported by RCT data: five were supported only by uncontrolled Phase II studies, two by uncontrolled open-label studies, and one by a literature analysis alone. Other limitations of the submitted data included the use of surrogate endpoints and inadequate durations of follow-up in relation to the natural history of the disease. A subsequent study by the same authors suggested that this situation persisted throughout the first decade after implementation of orphan drug legislation in the EU [5]. The limitations of the clinical evidence submitted to support marketing authorizations for orphan treatments have a number of implications. Poorly designed pivotal trials may contribute to a low rate of success for such applications both in the EU [4, 6] and the USA [7]. Furthermore, limited pivotal trial data, together with the high cost of many orphan treatments, may create difficulties in terms of reimbursement and market access [1, 8, 9]. As the number of orphan-designated treatments entering clinical practice increases, it is possible that the data supporting an application for marketing authorization may increase. Indeed, it has recently been suggested that submission of objective data on the natural
Page 2 of 7
history of a disease and the potential impact of the proposed new treatment could form an additional criterion for decision-making on market access and reimbursement policies [10]. A further consideration is that marketing authorizations based on limited clinical data could potentially expose the patient to increased risk of adverse events or lack of efficacy, compared with non-orphan treatments [11]. In view of these issues, the present study was performed to evaluate the pivotal clinical evidence packages presented in the European Public Assessment Report for orphan-designated treatments with an EMA marketing authorization.
Methods This study reviewed the clinical evidence packages for treatments approved by the EMA. All treatments included in the review belong to anatomical therapeutic chemical (ATC) category L (antineoplastic and immunomodulating agents); this category was chosen because it is the largest ATC category, containing almost 50 % of all orphan-designated treatments that have received marketing authorization from the EMA. Treatments were eligible for inclusion in the review if they had been approved after 31 December 2006 and had been evaluated in a comparative trial using at least one survivalbased clinical endpoint as opposed to short-term surrogate endpoints. The time limit was imposed to ensure that all included treatments had been evaluated by the EMA using similar criteria: it is possible that older treatments might have been evaluated using less stringent criteria than recently approved treatments. Similarly, the requirement for comparative studies using survivalbased endpoints was imposed because such studies can be considered the ‘gold standard’ for clinical trials in oncology and are recommended in United States Food and Drug Administration guidance [12]. Eligible treatments were compared in terms of the number of patients included in pivotal (‘main’) clinical trials submitted to support the application for marketing authorization, the cumulative duration of follow-up in the pivotal trials, expressed in patient-years, and the prevalence of the orphan condition. The number of patient-years of follow-up was calculated by multiplying the total number of patients in each study (across all treatment arms) by the study duration; where the study duration was not reported explicitly, Kaplan-Meier curves or data tables were used to estimate the duration of follow-up. Prevalence data for each orphan-designated condition were obtained from the relevant EMA Committee for Orphan Products public summary of opinion [3]: where these data were provided as the number of affected patients in the EU, this was converted to the rate per 10,000 based on the EU population at the time of orphan designation.
Winstone et al. Orphanet Journal of Rare Diseases (2015) 10:139
In addition to patient numbers and duration of followup, the quality of the pivotal trials for all orphan products approved by the EMA since 31 December 2006 was assessed by means of the Jadad scoring system [13]. In this system, a maximum of two points each are given for appropriate randomization and blinding, and a further point is given if all patients are adequately accounted for; thus, the maximum possible Jadad score is 5.
Results As of 1 February 2014, 68 treatments with 87 indications had received an EMA marketing authorization for orphan-designated conditions. The prevalence of the orphan indications varied markedly, from 0.00125/10,000 persons for N-acetylglutamate synthetase deficiency to
